Cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine (C-MSOQ), also known as cevimeline, is a pharmaceutical compound useful for the treatment of diseases of the central nervous system in mammals, particularly for the treatment of diseases due to disturbances of central cholinergic function and autoimmune disease such as Sjögren's syndrome.
U.S. Pat. No. 4,855,290 describes a process of making the intermediate 3-hydroxy-3-mercaptomethylene quinuclidine using a sodium hydroxide/dichloromethane system and hydrogen sulfide at 40° C. with 33 to 40% yield. Drawbacks of this process include providing the intermediate in very low yields due to the decomposition of the intermediate in the given reaction conditions, side product “diol” formation due to the susceptibility of the epoxide moiety to form diol with the sodium hydroxide solution at the recommended temperature, and the requirement of a continuous stream of hydrogen sulfide gas.
U.S. Pat. No. 5,571,918 describes the preparation of the intermediate 3-hydroxy-3-mercaptomethylene quinuclidine by a process of passing hydrogen sulfide gas continuously with a special type of catalyst, p-toluene sulfonic anhydride. Drawbacks of this process include an excess use of hydrogen sulfide gas by passing the hydrogen sulfide gas continuously for more than 6 hours and the requirement of an additional catalyst to complete the reaction. The amount of hydrogen sulfide used for the process is quite high—18 grams/per minute flow for 6 hours, therefore for a 13.9 gm batch of product the required quantity of hydrogen sulfide gas is 6.5 kg.
U.S. Published Patent Application No. 2008/0249312 describes a two way process of making the aforementioned intermediate using thiol-acetic acid, an industrially toxic chemical with a highly unpleasant odor, with a yield of approximately 60 to 70%. This process requires first making the salt and then isolating the salt to obtain the salt of the intermediate, which is then used for the subsequent reaction.
For the preparation of the cis isomer of cevimeline, U.S. Pat. No. 4,855,290 describes a process employing multiple recrystallization of the racemic 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine. Drawbacks of this process include lack of scalability due to multiple recrystallization steps and the requirement of enrichment of the cis-isomer from mother liquor involving chromatographic purification and isolation. In addition to unsuitability for commercialization, the resultant yield after several steps of purification is less than 10%.
U.S. Pat. No. 4,981,858 involves a resolution of enantiomers of cis and trans isomers of 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine individually by a tartaric acid resolution technique. There is no discussion regarding preparation and purification of the cis isomer from a racemic 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine.
U.S. Pat. No. 4,861,886 describes the conversion of pure trans 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine to the cis isomer under different conditions. However, no method is taught or disclosed for complete conversion of the trans isomer to the cis isomer. None of the techniques describe how to obtain pharmaceutical quality cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine.
U.S. Pat. No. 5,571,918 describes the conversion of racemic 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine to the cis isomer using stannic chloride as a catalyst. There is no teaching of any process or technique to obtain the cis isomer with greater than 98.5% purity when analyzed by HPLC.
Therefore, there is a need for an industrially viable process that achieves better yields of cis-form-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine and employs less expensive reagents and solvents, resulting in lower production costs. Furthermore, there is further a need for a process which can generate cis-form-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine of a pharmaceutically acceptable isomeric purity, i.e., at least 99.0% purity or greater, without the need for multiple tedious isolation, purification and/or separation steps.